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References | The CONSORT flow diagram.Violin plot on the frequency of days with any symptoms of URTI over 20 weeks of the trial. The horizontal line connects medians. Orange circles depict individual results. Error bars represent interquartile ranges.Violin plot of the medians of URTI symptoms’ average gravity scores over the 20 weeks of the trial. The horizontal line connects medians. Orange circles depict individual results. Error bars represent interquartile ranges.Violin plot of the number of URTI episodes scored with gravity 2 level over the entire study (21 weeks). The horizontal line connects medians. Orange circles depict individual results. Error bars present interquartile ranges.Days with abdominal side effects over the entire study. The horizontal line connects medians. Orange circles depict individual results. Error bars present interquartile ranges.Description of the major outcomes of the study.Baseline characteristics of analyzed children.The summary median reduction in the frequency of days with any URTI symptoms in the COL group versus the PBO group over various periods of the experiment.The summary AGS medians’ reduction in the COL group versus the PBO group over various periods of experiment. | PMC10459079 |
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1. Introduction | In this randomized, double-blind triple-crossover study (NCT05142137), the digestive tolerance and safety of a novel, slowly digestible carbohydrate (SDC), oligomalt, an α-1,3/α-1,6-glucan α-glucose-based polymer, was assessed in healthy adults over three separate 7-day periods, comparing a high dose of oligomalt (180 g/day) or a moderate dose of oligomalt (80 g/day in combination with 100 g maltodextrin/day) with maltodextrin (180 g/day), provided as four daily servings in 300 mL of water with a meal. Each period was followed by a one-week washout. A total of 24 subjects (15 females, age 34 years, BMI 22.2 kg/mCarbohydrates represent a large family of heterogenous molecules derived from carbon, hydrogen, and oxygen that can be naturally occurring or derived. Dietary carbohydrates, also called “glycemic carbohydrate”, are a major macronutrient for both humans and omnivorous animals, and it is recommended that adults in western countries obtain approximately half their daily caloric intake from dietary carbohydrates. This is illustrated by a variety of dietary guidelines, such as The Dietary Guidelines for Americans, which recommend that carbohydrates make up 45–65% of total daily calories in people aged two years old and older [Digestible carbohydrates are an important source of energy for most mammalian cells, including as the primary source of fuel for the brain. They are also used as sweeteners (mostly sucrose, glucose, and fructose) and to add texture, bulk, and increase appearance and preservation/shelf life of many foods [A growing interest in the health and food industry is therefore focused on the use of complex dietary carbohydrates that are slowly digested and can substitute, or at least reduce the amount of, the less-desired rapidly digestible carbohydrates. Unlike fiber, defined by the WHO and Codex Alimentarius as all carbohydrates that are neither digested nor absorbed in the small intestine and which have a degree of polymerization (DP) of ten or more monomeric units [There have been several innovations and developments that have aimed to identify an appropriate SDC [This study evaluated the tolerability of oligomalt, a novel SDC (formerly also known as alternan saccharide (AS 15)) with a DP of approximately 15 relative to a rapidly available carbohydrates (maltodextrin), in healthy individuals. Since it is anticipated that oligomalt is slower to digest than a readily available carbohydrate (such as corn syrup or maltodextrin), albeit still fully digestible [ | PMC10305601 |
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2. Materials and Methods | PMC10305601 |
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2.1. Study Design and Participants | In this single-centre, randomized-controlled, double-masked, three-period, three-intervention, cross-over study, participants consumed two different doses of the investigational product, or a control product, for 7 consecutive days. The study protocol was approved by the Institutional Review Board of Orange County Research Center, USA, and Temasek Polytechnic, Glycemic Index Research Unit, Singapore, and the study was carried out in compliance with the Harmonized Tripartite Guideline for Good Clinical Practice from the International Conference on Harmonisation [ | PMC10305601 |
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2.2. Inclusion and Exclusion Criteria | Eligible volunteers of any gender were enrolled in the study if, following informed signed consent, they fulfilled the inclusion criteria. The key inclusion criteria were as follows: male or female, self-reported to be healthy, age 18–65 years, BMI 18.5–29.9 kg/mA further exclusion criterion was the habitual consumption of more than four servings per day of high-fiber food or an extreme dietary habit low in carbohydrates. The former was pragmatically assessed with the habitual dietary fiber intake short food frequency questionnaire (DFI-FFQ) [Moreover, participants who had any score of a “severe” symptom for any of the symptoms included in the Gastrointestinal Symptom Rating Scale (GSRS), a validated questionnaire exploring the presence and severity of gastrointestinal (GI) symptoms over the previous 7 days [ | PMC10305601 |
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2.3. Study Conduct and Schemes | During the different 7-day sequences with investigational product consumption (Schematic study illustration in the Given that the caloric load was 180 kcal per serving (or 720 kcal total/day), all participants received general nutritional recommendations and were asked to pay specific attention to their consumption of grains and cereals and sugar-rich foods and beverages since the study contributed to an excess intake of energy. | PMC10305601 |
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2.4. Interventional Products | The maltodextrin used in this study was “GlucidexThe oligomalt used in this study was comprised of small quantities of free sugars (<5.5% sugars, of which <0.2% is fructose and 5.3% is leucrose but zero glucose, sucrose, isomaltose, or maltose), with an average ± standard deviation DP of 16.5 ± 0.1 and a molecular weight of 2.7 ± 0.02 kDa.The test products were provided as sachets (i.e., powders with approx. 4% moisture), each containing 45 g of carbohydrates (either 45 g oligomalt, 20 g oligomalt + 25 g maltodextrin, or 45 g maltodextrin), which were to be dissolved in 300 mL water and taken together with a meal. | PMC10305601 |
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2.5. Endpoints | The predefined primary objective of this trial was to investigate the gastrointestinal tolerability of oligomalt when consumed daily for 7 consecutive days at two different dosages (80 g/day in combination with 100 g of maltodextrin/day and 180 g/day, respectively) as compared to maltodextrin (180 g/day), based on the GSRS questionnaire [ | PMC10305601 |
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2.6. GSRS | abdominal pain, reflux, diarrhea, constipation | GI DISORDERS | The GSRS is a 15-item instrument designed to assess the symptoms associated with common GI disorders. It has 5 subscales (reflux, diarrhea, constipation, abdominal pain, and indigestion). Responses to the items range from 1 to 7, with higher scores representing more discomfort (1: No discomfort at all; 2: Slight discomfort; 3: Mild discomfort; 4: Moderate discomfort; 5: Moderately severe discomfort; 6: Severe discomfort; 7: Very severe discomfort). It has been used in multiple studies across multiple conditions and is well validated [ | PMC10305601 |
2.7. Bristol Stool Scale | The Bristol Stool Scale is a scale that classifies stools, ranging from the hardest to the softest, and defines 7 types of stool: hard (types 1–2), normal (types 3–5), and loose stools (types 6–7) [ | PMC10305601 |
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2.8. Sample Size Estimation | The sample size was determined based on previous safety studies carried out with other SDCs on feasibility considerations at the investigational site, as well as considerations pertaining to not exposing participants unnecessarily to study products and study procedures. Thus, no formal sample size calculation was performed; however, a total of | PMC10305601 |
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2.9. Blinding and Randomisation | Each participant consumed all three test products in a sequence ( | PMC10305601 |
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2.10. Product Administration | The investigational product and the comparator were packed as individual doses of 45 g, and each individual was to take the product 4 times daily for one week. Participants were asked to dissolve the powder in 300 mL of water at room temperature and were also asked to take at least 3 of their 4 daily doses with a meal at timepoints 08:00 ± 2 h, 12:00 ± 2 h, 16:00 ± 2 h, and 20:00 ± 2 h (minimum time interval between individual product intakes was ≥3 h). Upon ingestion of the last dose on day 7, a minimum washout of 7 days was required before the next intervention period began, in random sequence, as determined by the randomization system (3 × 3 crossover). | PMC10305601 |
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2.11. Data Collection | The participant-reported outcomes. i.e., questionnaires, were collected using the iMedidata patient cloud (i.e., in a remote set up), and each participant received a unique activation code that needed to be used to generate their personal unique pin. Participants were asked to report the following on a daily basis: product compliance, GSRS, and Bristol Stool Scale. | PMC10305601 |
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2.12. Statistical Analysis | The effects of the interventions on the GSRS (overall effect, subdomain effects, and effects related to intervention period) and Bristol Stool Scale were assessed using a linear mixed model, and they accounted for information from all 7 days of intervention. A | PMC10305601 |
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3. Results | INFLAMMATION, ADVERSE EVENT | The first participant was screened 16 August 2021, and the third intervention sequence ended on 11 October 2021. A total of 24 subjects were enrolled, randomized, and had at least one investigational product intake. Two subjects dropped out, which resulted in 22 subjects completing all periods and sequences, reflecting a high adherence to study procedures and product compliance. The reasons for participants dropping out were that one person had an adverse event after the first period (inflammation of the knee), which was not related to the product, and the other withdrew from the study without further explanation. All 24 participants were included in the analysis set both for efficacy and safety.The population, with mean age 34 years, was healthy ( | PMC10305601 |
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3.3. Safety and Adverse Events | ADVERSE EVENT | Adverse events ( | PMC10305601 |
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4. Discussion | diarrhea | This study, in 24 healthy adult volunteers (15 females, age 34 years, BMI 22.2 kg/mIn consideration of a “minimal important difference” (MID), which is the smallest difference in the scores that is perceived as significant by the clinician or the patient [The evolutive the GSRS pattern, with tolerability developed over time, therefore underscores the product’s tolerability and safety profile, and is also supported by a previous investigation of oligomalt that found that a 33 g dose was completely metabolized as assessed with a hydrogen breath test over 4 h [Another observation from this study was that there was no clinically meaningful differential effect on stool consistency according to the Bristol Stool Scale. However, the high-dose oligomalt resulted in a slight signal for increase in loose stool, aligned with higher GSRS subdomain diarrhea score. Similar to the tolerability, the Bristol Stool Scale score was subject to a GI adaptation, as indicated by the intervention sequence analysis that found that the stool frequency was numerically lower at the third sequence compared to the first. | PMC10305601 |
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Limitations and Strengths | BLOOD | The key limitation of this study was that exposure to individual products did not extend beyond 7 consecutive days. However, in reality, participants were exposed to oligomalt for at least 14 days of the overall 21 days of intervention, i.e., over two study sequences, albeit with different doses and a washout period, which provides reassurance with respect to longer-term tolerability. Additionally, this study was a single-center study, involving a limited number of participants of predominantly Caucasian origin who did not have any underlying health conditions, including inflammatory bowel disease or gastrointestinal issues, at relatively young age. Blood or other biomarkers which could be relevant, e.g., gut microbiota, were also not collected nor analyzed. Furthermore, oligomalt was consumed with water only; whereas in reality, oligomalt will likely be consumed in a complex food matrix, which usually translates to better tolerability [ | PMC10305601 |
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5. Conclusions | This study evaluated the GI tolerability of a novel SDC, oligomalt. Oligomalt was well tolerated when taken at a moderate (80 g/day) or high (180 g/day) dose, with no effect on stool frequency. An evolutive pattern with decreasing GI symptoms was seen with exposure over time, with normative scores being reached following 2–3 weeks of exposure to oligomalt. Given oligomalt’s healthier composition, it appears to be a potential viable alternative carbohydrate source for nutritional products, when also taking into account the implications for blood glucose, the insulin response, and overall metabolic health. | PMC10305601 |
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Supplementary Materials | The following supporting information can be downloaded at: Click here for additional data file. | PMC10305601 |
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Author Contributions | Conceptualization, M.v.E., C.D., A.O. and J.S.L.-A.; Methodology, O.E.J., M.v.E., A.R., A.L. and C.D.; Project administration, J.S.L.-A.; Funding acquisition, M.v.E. and J.S.L.-A.; Formal analysis, O.E.J., A.R. and A.L.; Investigation, O.E.J. and F.D.; Resources, D.C., M.v.E., A.R., G.U., K.T. and J.S.L.-A.; Supervision, O.E.J. and M.v.E.; Writing—original draft preparation, O.E.J.; Visualization, O.E.J.; Writing—review and editing, O.E.J., D.C., M.v.E., A.R., A.L., F.D., G.U., C.D., A.O., K.T. and J.S.L.-A. All authors have read and agreed to the published version of the manuscript. | PMC10305601 |
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Institutional Review Board Statement | humain | The study was conducted in accordance with the Declaration of Helsinki and approved by the “Commission cantonale d’éthique de la recherche sur l’être humain du Canton de Vaud” with reference number 2021-00585. It was registered at | PMC10305601 |
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Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10305601 |
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Data Availability Statement | Original data supporting these results are available on request to the corresponding author for reasonable purposes. | PMC10305601 |
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Conflicts of Interest | Odd Erik Johansen, Maximilian von Eynatten, Carmine D’Urzo, and Kate Thorne are employed by Nestlé Health Science, Lausanne, Switzerland. Delphine Curti, Andreas Rytz, Anirban Lahiry, Frederik Delodder, and Audrey Orengo are employed by Nestlé Research, Lausanne, Switzerland. Gerhard Ufheil is employed by Nestlé Research and Development, Konolfingen, Switzerland. Jaclyn S. Lerea-Antes is employed by Nestlé Health Science, Bridgewater, United Sates. | PMC10305601 |
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References | distensionAbdominal painAbdominal pain | ADVERSE EVENT, EVENTS | Effect on total score for Gastrointestinal Symptom Rating Scale by intervention, regardless of intervention sequence. The figure shows the mean (95% CI) (Subdomain scores for the Gastrointestinal Symptom Rating Scale (GSRS) by intervention, regardless of intervention sequence. The figure shows the mean (95% CI) (Total score for Gastrointestinal Symptom Rating Scale by period regardless of intervention. The figure shows the mean (95% CI) (Total Gastrointestinal Symptom Rating Scale by intervention and intervention period. The figure shows the mean Gastrointestinal Symptom Rating Scale (SD) (Bristol Stool Scale by intervention in the overall population (FAS). The figure shows the mean (95% CI) (Stool frequency by intervention and period. The figure shows mean stool frequency (SD) (Baseline characteristics of the study population: Abbreviations: SD—standard deviation; kg—kilogram; mmHg—millimeter of mercury.Adverse events (AEs). Safety analysis set: subjects with events (%).MildModerateSevereProbableUnlikelyUnrelatedAbdominal distensionAbdominal painAbdominal pain upperConstipationDiarrheaFeces discoloredFlatulenceGastric disorderGI painGI sounds abnormalNauseaVomiting | PMC10305601 |
Abstract | PMC10166179 |
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Background | tumor, PDAC, pancreatic ductal adenocarcinoma | PANCREATIC DUCTAL ADENOCARCINOMA, TUMOR | In preclinical pancreatic ductal adenocarcinoma (PDAC) models, inhibition of hepatocyte growth factor (HGF) signaling using ficlatuzumab, a recombinant humanized anti-HGF antibody, and gemcitabine reduced tumor burden. | PMC10166179 |
Methods | PDAC | Patients with previously untreated metastatic PDAC enrolled in a phase Ib dose escalation study with 3 + 3 design of 2 dose cohorts of ficlatuzumab 10 and 20 mg/kg administered intravenously every other week with gemcitabine 1000 mg/m | PMC10166179 |
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Results | toxicities | Twenty-six patients (sex, 12 male:14 female; median age, 68 years [range, 49-83 years]) were enrolled, 22 patients were evaluable. No dose–limiting toxicities were identified ( | PMC10166179 |
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Conclusion | hypoalbuminemia, edema | HYPOALBUMINEMIA, EDEMA, PANCREATIC DUCTAL ADENOCARCINOMA | In this phase Ib trial, ficlatuzumab, gemcitabine, and albumin-bound paclitaxel were associated with durable treatment responses and increased rates of hypoalbuminemia and edema.This article evaluates the safety profile and clinical efficacy of ficlatuzumab (AV-299), in combination with standard systemic chemotherapy of gemcitabine and albumin-bound paclitaxel, in patients with metastatic pancreatic ductal adenocarcinoma. | PMC10166179 |
Implications for Practice | antibody reduced, tumor, pancreatic adenocarcinoma | PROLIFERATION, TUMOR, PANCREATIC ADENOCARCINOMA | Dysregulation of the hepatocyte growth factor (HGF)/c-Met signaling pathway can lead to aberrant cell proliferation, drug resistance, and promotion of cell migration and invasion. In pre-clinical pancreatic adenocarcinoma models, ficlatuzumab, an anti-HGF monoclonal antibody reduced tumor burden in combination with gemcitabine. In this multi-center, phase Ib dose escalation study, 2 dose cohorts of ficlatuzumab (10 and 20 mg/kg intravenously every 2 weeks) were administered with gemcitabine and | PMC10166179 |
Background | human pancreatic cancer stem cell marker., PDAC, aggressive disease | PANCREATIC DUCTAL ADENOCARCINOMA, SOLID TUMORS | Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with poor clinical outcomes. In a recent report, Li et al identified c-Met as a potential novel human pancreatic cancer stem cell marker.Ficlatuzumab, a humanized immunoglobulin G1 monoclonal antibody that targets HGF, is a HGF-c-Met inhibitor which has been evaluated in multiple studies in patients with advanced solid tumors. | PMC10166179 |
Methods | PMC10166179 |
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Patients | infection, major cancer | PANCREATIC CARCINOMA, CEREBRAL METASTASES, METASTATIC PANCREATIC CANCER, INFECTION, CARDIAC DISEASE, ONCOLOGY, PERIPHERAL NEUROPATHY, CHRONIC DIARRHEA | Patients were eligible if they were 18 years of age or older and had histologically or cytologically confirmed, measurable by RECIST version 1.1, previously untreated metastatic PDAC. Other inclusion criteria were an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 and adequate bone marrow (granulocyte count >/= 1500 per cubic millimeter; and platelet count >/= 100 000 per cubic millimeter), liver (bilirubin </= 1.5 times the upper limit of the normal range), and renal (creatinine >/= 1.5 times the upper limit of the normal range OR creatinine clearance >/= 60 mL/minutes/1.73 mPrior systemic treatments were permitted if they received (1) adjuvant treatment after surgical resection with single-agent gemcitabine, gemcitabine/capecitabine, or 5-fluorouracil/leucovorin if completed >12 months before enrollment; (2) adjuvant radiation with or without chemotherapy sensitization with 5-fluorouracil, capecitabine, or gemcitabine if completed > 12 months before enrollment; (3) neoadjuvant treatment prior to surgical resection with single-agent gemcitabine or 5-fluorouracil/leucovorin/oxaliplatin/irinotecan if completed >12 months before enrollment.Exclusion criteria were an endocrine or acinar cell pancreatic carcinoma, previous chemotherapy for locally advanced or metastatic pancreatic cancer, radiotherapy for measurable lesions, concurrent use of any other anti-cancer therapy, cerebral metastases, history of another major cancer, active infection, chronic diarrhea, pre-existing peripheral neuropathy (CTCAE grade 2 or higher), clinically significant history of cardiac disease, and pregnancy or breast-feeding. | PMC10166179 |
Treatment Program | tumor, death, Tumor, Cancer | TUMOR, TUMOR, ADVERSE EVENT, BLOOD, CANCER | This was a multi-center, phase Ib dose escalation study with a 3 + 3 design conducted at 2 Harvard Cancer Center sites, namely Dana-Farber Cancer Institute/Brigham Cancer Center and Massachusetts General Hospital (Diagram of patients enrolled.Radiologic tumor assessments included contrast-enhanced CT scan of the chest, abdomen and pelvis or MRI abdomen, and pelvis with contrast-enhanced CT chest. Radiologic response was classified according to RECISTv1.1. Tumor markers, carcinoembryonic antigen (CEA) and CA 19-9, were followed every 4 weeks, or at the initiation of each chemotherapy cycle. Patients were followed for 6 months after removal from protocol therapy or until death, whichever occurred first. Participants removed from protocol therapy for unacceptable adverse event(s) were followed until resolution or stabilization of the adverse event.Blood samples were taken to assess circulating HGF measurements on day 1 of cycles 1 and 2. The Viracor Eurofins Clinical diagnostics plasma assay for quantification of HGF is a sandwich ELISA performed in a microtiter plate format. A standard curve is used to calculate the concentration of HGF in each test sample. The assay range is 0.6-24 ng/mL.Pre-treatment tissue biopsies, which consisted of 2 needle cores for formalin-fixation, paraffin embedding, were collected to analyze pre-treatment histology and c-Met pathway activation. Initial analysis by immunohistochemistry (IHC) of HGF, c-MET, and p-MET was performed to assess presence of direct targets of ficlatuzumab. | PMC10166179 |
Statistical Analysis | Cancer | CANCER | This study evaluated the safety and tolerability of ficlatuzumab when given with standard chemotherapy with the aim of determining the maximum tolerated dose (MTD) of ficlatuzumab in combination with gemcitabine and The study (NCT03316599) was approved by the Dana-Farber Cancer Institute institutional review board and conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent before any study procedures. | PMC10166179 |
Results | PMC10166179 |
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Patient Characteristics | Between January 2018 and April 2019, a total of 26 patients enrolled in the study. Baseline characteristics of the patients are listed in Demographics.
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Treatment, DLT, and Determination of Maximum Tolerated Dose (MTD) | toxicity, DLTs | In the phase Ib study, a minimum of 3 enrolled patients per dose level was planned. No DLTs were reported in the first 3 patients enrolled at dose level 1 (ficlatuzumab 10 mg/kg) or 3 subsequent patients enrolled at dose level 2 (ficlatuzumab 20 mg/kg). Therefore, the regimen of gemcitabine 1000 mg/mIn total, 25 patients were assessable for toxicity, as summarized in Adverse toxicity profile (CTCAE v4.0) attributed to ficlatuzumab ( | PMC10166179 |
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Secondary Endpoints: Response Rate, Progression-Free Survival, Overall Survival | PD | DISEASE, BEST | Of the 21 patients treated at the MTD, 19 patients met criteria for response assessment per protocol. Two patients were not evaluable because they withdrew from therapy or discontinued treatment due to physician decision. Best responses by RECIST criteria were: 6 (29%) partial responses; 12 patients (57%) with stable disease, and 1 (5%) patient with progression prior to completion of 1 cycle of therapy (Best response by RECIST 1.1. *The one patient noted as a PD had a target lesion that met criteria for stable disease, but a non-target lesion fulfilled criteria for PD, so the overall response was PD.
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Treatment Exposure | death | The median duration of treatment was 7.1 months (range, 0-24.9 months); and median number of cycles started was 7 cycles (range, 1-27). Patients were followed for 6 months after removal from protocol therapy or until death, whichever occurred first. The median follow-up time was 9.1 months (range, 0.3-26.3 months). Among the 25 patients, 48% of patients required reductions in | PMC10166179 |
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Association Between Toxicities and Outcomes | toxicity, hypoalbuminemia, toxicities, peripheral edema | HYPOALBUMINEMIA, PERIPHERAL EDEMA | Since 52% of participants developed any grade hypoalbuminemia and 48% developed any grade peripheral edema while on therapy, an analysis was performed to assess the association between these toxicities and clinical outcomes. Across RR, PFS, and OS, no statistically significant associations were identified among patients who experienced hypoalbuminemia or peripheral edema, although the 95% CIs were wide (Association between toxicity and RR, PFS, and OS.
Abbreviations: HR, hazard ratio; PR, partial response. | PMC10166179 |
Correlative Analysis | tumor | DISEASE, TUMOR | We evaluated 11 serum sample pairs for HGF prior to initiation of treatment on days 1 and 1 of cycle 2. Of the 11 pairs, 9 were evaluable for response at MTD. There was no association between C1D1 HGF values and best response (Fourteen of the patients had sufficient samples from pre-treatment tissue biopsies for immunohistochemistry analysis to characterize pre-treatment histology and assess c-Met pathway activation. Of the 14 patients, 3 received ficlatuzumab at 10 mg/kg and 11 received ficlatuzumab at 20 mg/kg. Interrogation for markers of c-Met pathway activation included analysis of HGF, c-Met, p-Met, p-ERK, p-Akt, and p-S6K expression by immunohistochemistry (IHC) in tumor cells. Among 9 patients with available response data, H-score for p-Met was associated with disease response rate (The correlation between p-Met and clinical response. | PMC10166179 |
Discussion | hypoalbuminemia, Edema, cancer | HYPOALBUMINEMIA, PROLIFERATION, CANCER, EDEMA, SECONDARY, METASTASES | Dysregulation of the HGF/c-Met signaling pathway can lead to aberrant cell proliferation, drug resistance, and promotion of cell migration and invasion.Edema and hypoalbuminemia are known side effects of HGF/c-Met inhibitors, including ficlatuzumab.With respect to the secondary objectives, this study showed that the addition of ficlatuzumab to the combination of gemcitabine and c-Met pathway activation has been associated with cancer cell proliferation and metastases, | PMC10166179 |
Conclusion | In this study, the recommended dose of ficlatuzumab when combined with gemcitabine and | PMC10166179 |
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Acknowledgments | Pancreatic Cancer | PANCREATIC CANCER, CANCER, CANCER, PANCREATIC | Harvard P30 CCSG grant number. AR acknowledges support from NIH 2R01 DK060694 and NIH 5P30013696. B.M.W. acknowledges support from the Hale Family Center for Pancreatic Cancer Research, Lustgarten Foundation Dedicated Laboratory program, NIH grant U01 CA210171, NIH grant P50 CA127003, Stand Up to Cancer, Pancreatic Cancer Action Network, Noble Effort Fund, Wexler Family Fund, Parsons Pancreatic Cancer Early Detection Fund, and Promises for Purple. | PMC10166179 |
Statement of Ethics | Cancer | CANCER | The study was approved by the Dana-Farber/Harvard Cancer Center Institutional Review Board IRB. The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. The subjects provided their WRITTEN informed consent to participate in the IRB approved protocol 17-406. B.M.W. has received research funding from Celgene and Eli Lilly, and consulting fees from Celgene, Grail, and Mirati, unrelated to the present work. | PMC10166179 |
Funding | This investigator-sponsored study received funding from AVEO Pharmaceuticals. | PMC10166179 |
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Conflict of Interest | Alentis | ONCOLOGY | Kimberly Perez was a one-time advisory board member for Lantheus and QED/Helsinn. James M. Cleary receives research funding to his institution from Merus, Roche, and Bristol Myers Squibb; he receives research support from Merck, AstraZeneca, Esperas Pharma, Bayer, Tesaro, Arcus Biosciences, and Apexigen; he has also received honoraria for being on the advisory boards of Syros Pharmaceuticals, Incyte, and Blueprint Medicines. Lawrence Blaszkowsky reports that spouse has equity in Pfizer. Peter Enzinger is a consultant for ALX Oncology, Arcus Bioscience, Astellas, AstraZeneca, Blueprint Medicines, Chimeric Therapeutics, Celgene, Coherus, Daiichi-Sankyo, Five Prime, Ideaya, Istari, Legend, Lilly, Loxo, Merk, Novartis, Ono, Servier, Taiho, Takeda, Turning Point Therapeutics, Xencor, and Zymeworks. Marios Giannakis reported research funding from Merck, Servier, and Janssen. Lipika Goyal serves on the Scientific Advisory Committee for Alentis Therapeutics AG, Black Diamond, Exelixis, Genentech, H3Biomedicine, Kinnate, Incyte Corporation, QED Therapeutics, Merck, Servier, Sirtex Medical Ltd, Surface Oncology, Taiho Oncology Inc., TranstheraBio; on the DSMC for AstraZeneca; and as a consultant for Alentis Therapeutics, Genentech, Exelixis, Incyte Corporation, QED Therapeutics, Servier, Sirtex Medical Ltd, Taiho Oncology Inc., TranstheraBio, and Tyra Biosciences. Jeffrey A. Meyerhardt has served as an advisor/consultant to Merck Pharmaceutical and COTA Healthcare. Douglas Rubinson serves on the Scientific Advisory Board for AxialTx Consulting, Boston Scientific, and Instylla. Matthew B. Yurgelun has received research funding from Janssen Pharmaceuticals and fees for peer review services from UpToDate. Victoria Germon reports that spouse is an employee of Pfizer. Srivatsan Raghavan holds equity in Amgen. Andrew J. Aguirre reports consulting for Arrakis Therapeutics, Merck, Inc., Syros Pharmaceuticals, Servier, Mirati Therapeutics, Boehringer Ingelheim, T-Knife Therapeutics, AstraZeneca, Reactive Biosciences, Revolution Medicines, Anji Pharmaceuticals, and Riva Therapeutics; research funding from Mirati Therapeutics, Revolution Medicines, Bristol-Myers Squibb, Novartis, Eli Lilly, Syros Pharmaceuticals, Deerfield Management, and Riva Therapeutics. Michael Needle reports that, at the time this work was done, he was a full-time employee and shareholder in Aveo Oncology. Brian M. Wolpin reports receipt of grant funding to institution from Celgene, Eli Lilly, Novartis, and Revolution Medicine (all unrelated to the present work), and consulting for GRAIL and Mirati. The other authors indicated no financial relationships. | PMC10166179 |
Author Contributions | Conception/design: K.P., A.C., C.W., S.R., B.B., K.D., J.P., A.A., M.N., A.K.R., B.M.W. Provision of study material or patients: K.P., J.M.C., C.W., T.A., L.B., P.E., M.G., L.G., J.A.M., D.R., M.B.Y., W.G., B.G., B.M.W. Collection and/or assembly of data: K.P., A.C., N.H., V.G., D.S., A.K.R., B.M.W. Data analysis and interpretation: K.P., A.M.C., J.M.C., N.H., L.B., S.R., B.B., K.D., J.P., A.A., A.K.R., B.M.W. Manuscript writing: K.P., J.M.C., N.H., A.K.R., B.M.W. Final approval of manuscript: All authors. | PMC10166179 |
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Data Availability | The data underlying this article are available in the article and in its online supplementary material. | PMC10166179 |
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References | PMC10166179 |
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Background: | mental disorder | Informal settlements are high density areas in and around cities, characterized by a lack of formal planning and basic amenities, being known in South Africa for high levels of mental disorder driven by violence, and complex social and economic challenges. In particular, young men’s poor mental health goes untreated, with relatively few evidenced-based interventions available in this setting. | PMC10657496 |
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Aim: | This cluster randomized controlled trial investigated the effectiveness of Stepping Stones and Creating Futures (SS/CF), a participatory gender transformative and economic empowerment intervention, on the mental health of young men living in South African informal settlement. | PMC10657496 |
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Methods: | post-traumatic stress, anxiety, PTS | A total of 674 young men ages 18 to 30 years were recruited in 34 clusters in Durban’s urban informal settlements. Clusters were randomly allocated (1:1) to either the experimental SS/CF or control arm and participants were followed-up over 24-months. Intention-to-treat analysis based on generalized estimating equations (GEE) were fitted to quantify the impact of SS/CF on the men’s anxiety and post-traumatic stress (PTS) symptomatology. | PMC10657496 |
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Results: | anxiety | At end of the 24 months follow-period, anxiety (adjusted odds ratio [aOR]: 0.62, | PMC10657496 |
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Conclusion: | anxiety, PTS | SS/CF, a gender transformative and livelihoods strengthening intervention designed to address poverty and other socio-economic challenges in informal settlements reduced anxiety and PTS among men with mental health challenges living in informal settlements. | PMC10657496 |
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Introduction | Trauma, anxiety, traumatic | SECONDARY | Poor mental health continues to be pervasive in sub-Saharan Africa (SSA; Informal settlements in South Africa are contextually distinct, initially being consequences of the country’s pre-democracy regime’s discriminatory migrant labour and spatial policy, they continue to persist. Previous studies indicate that these settlements face a range of health and social issues, including high crime rates and HIV (The social, economic and physical settings in which people live greatly influence their mental health. Similar to other low- and middle-income countries (LMICs) (Economic distress: Poverty and a lack of job prospects are frequent experiences in informal settlements (Crime and violence: Gang activity and other forms of violence are frequently found in high concentrations in urban informal communities (Social isolation: It might be challenging for young males to build social networks and contacts in informal settlements because of their density and lack of social infrastructure (Discrimination: There is a chance that young males in slum areas will be treated unfairly because of their social standing or other characteristics (Limited access to healthcare: Being a common characteristic of informal settlements (Trauma: Being exposed to traumatic experiences like natural disasters, neighborhood violence or conflict can have a long-lasting effect on mental health. Trauma has affected the lives of many young men who live in informal settlements (Given the high levels of poor mental health among young men in urban informal settlements, likely driven by social circumstances, evaluating interventions that may promote positive mental health is critical (The Stepping Stones and Creating Futures intervention combined a gender transformative intervention (Stepping Stones) with a livelihoods intervention (Creating Futures), which sought to reduce perpetration of IPV in young men living in urban informal settlements (Gibbs et al., 2017). Gender transformative interventions aim to change deeply embedded gender norms, roles and expectations rather than merely reinforcing or maintaining them as a means of combating gender inequality and advancing gender equity. Livelihood interventions are economic empowerment tools used to deliver sustainable development by tackling the multifaceted problems of poverty. We conducted a secondary post-hoc analysis of this trial to investigate the intervention’s impact on mental health (i.e. anxiety and PTS).Urban informal settlements are rapidly expanding globally and in South Africa, with over 850 million ( | PMC10657496 |
Methods | PMC10657496 |
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Study design | SECONDARY | Using cohort data gathered at baseline and end-line for the main trial analysis of the impact of SS/CF among young men recruited into the study, we conducted a secondary post-hoc investigation. The original data set for the trial was provided by the research team allowing extraction of relevant variables. | PMC10657496 |
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Study setting and population | This study entailed analyses of a cluster randomized controlled trial (RCT) that evaluates whether Stepping Stones and Creating Futures (SS/CF) reduces poor mental health among young men (18–30 years) in informal settlements. Clusters were identified by areas within informal settlements that were demarcated by pre-existing divisions or partitions such as natural barriers (e.g. a major road or waterway). The two-arm randomized controlled trial took place in urban informal settlements in Durban, KwaZulu-Natal Province and was conducted in collaboration with Project Empower (a local NGO that works to address gender-based violence). With over three million residents ( | PMC10657496 |
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Intervention and data collection | EVENTS, RECRUITMENT | SS/CF is a community-based intervention originally designed to reduce IPV (although it has components that target mental health). The Stepping Stones component is focused on gender transformation and consists of 10 three-hour sessions (30 hours total), administered by trained peer facilitators to single-sex groups of 14 to 20 people, which was conducted over a period of 6 to 8 weeks. It employed participatory learning methods, such as critical thinking and incorporated the participants’ daily lives into the exercises. Among other topics covered, they targeted at improving social connections, this being the context in which actions occur while engaging with others. Creating Futures is focused on economic empowerment that consists of 11 three-hour sessions (33 hours in total) administered to the same single-sex groups as Stepping Stones. Setting livelihood priorities, dealing with crises, investing and saving, finding and maintaining jobs and balancing work aspirations were among the topics discussed, as reported elsewhere (At the time of recruitment and informed consent, individuals were not blinded to the study arm. Despite the possibility of recruitment bias, participant welfare and project staff security were more at risk due to previous events of being promised support but not getting it and high levels of mistrust surrounding research, which are frequently found in marginalized communities. | PMC10657496 |
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Randomization and sampling procedure | Stepping stones | A cluster RCT, consisting of intervention and control groups (1:1 ratio), was conducted from September 2016 to October 2018. The intervention arm was administered with SS/CF, while the control arm was on a waitlist to receive the intervention after the final data collection. Once clusters were identified, randomization into intervention and control arms was carried out at the cluster level. Each cluster was assigned a cluster number, and the data analyst used a numbering system to randomize the clusters. When the numbers were randomly assigned to the clusters, the analyst was unaware of which cluster number belonged to which assignment group.Project Empower workers identified potential study participants from clusters using snowball and purposive sampling techniques. The following inclusion criteria were used to enrol participants: (1) aged 18 to 30 years, (2) not currently in formal employment or education (3) resident within specified informal settlement clusters and (4) ability to communicate in English, isiZulu or isiXhosa. Those who (4) were unable or unwilling to provide written informed consent were excluded from participating in the study. Interested participants completed the informed consent form, with approximately 20 young men being sought from each of the 34 clusters (17 clusters in each of the arms). The informed consent consisted of the nature and purpose of the study, a detailed explanation of procedures to be followed and the risks, costs and potential benefits of involvement. Participants were made aware that their participation was voluntary, and that any information obtained from them would be kept confidential. Study participants were re-interviewed by professional research personnel who are proficient in English, isiZulu and isiXhosa at baseline, 12 and 24 months. The interviews were conducted using questionnaires that were forward and back translated from English into IsiZulu and IsiXhosa, with Stepping stones and creating futures CONSORT diagram for men. The flow diagram consists of a timeline that reports the enrolment, allocation, follow-up of clusters and study participants at each arm. 34 clusters were recruited and randomized to either the intervention (SS/CF) or control arm. After intervention was administered, follow-up was done on each arm after 12 months and after 24 months. | PMC10657496 |
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Ethical consideration | The University of KwaZulu-Natal Biomedical Research Ethics Committee (BFC043/15) and the South African Medical Research Council Ethics Review Committee (EC006-2/2015) provided ethics approval to conduct the main trial. All participants provided written informed consent. The use of data for the present study was approved by the Biomedical Research Ethics Committee at the University of KwaZulu-Natal (00002795/2021). The trial was registered with ClinicalTrials.gov (NCT03022370). | PMC10657496 |
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Measures | PMC10657496 |
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Outcome variables | Anxiety, anxiety, post-traumatic stress disorder, PTSD, Trauma, post-traumatic stress | Anxiety and post-traumatic stress were the main outcomes of the study, with two validated tools being used to measure the participants’ levels of both at 12 months and 24 months. Anxiety symptoms were identified by the 7-item General Anxiety Disorder-7 (GAD-7) scale that was developed to assess levels of anxiety over the past two weeks (The Harvard Trauma Questionnaire (HTQ), a 16-item measure validated in other South African populations (The HTQ was recoded into binary variable where mean HTQ scores >2.5 were classified as having probable post-traumatic stress disorder [PTSD] ( | PMC10657496 |
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Baseline socio-demographic and other descriptors | PTSD, Trauma, trauma | DISORDERS, EVENT, EVENT, EVENTS, EVENTS | In addition to socio-demographic information (e.g. age, marital status, education and employment status) and intervention assignment (i.e. study arm), six variables are worth noting for this current investigation, as they represent some of the challenges faced in informal settlements in South Africa: food security, crime participation, adverse childhood events, exposure to trauma event, gender equitable men scale and unhealthy alcohol use.Food security was measured using the Household Hunger Scale (HHS), having been used in South Africa elsewhere (Crime participation entailed the use of the 10-item participation in crime measure, been validated and utilized in rural South Africa elsewhere (Adverse Childhood Events (ACE) were evaluated using the 13-item scale Childhood Trauma Questionnaire (CTQ), having been adapted for use in South Africa (Exposure to trauma event was assessed through the revised Life Event Checklist from the PTSD Checklist, which has been validated in various South African communities (Gender Equitable Men Scale (GEMS) was used to measure masculinities and gender attitudes, being designed to generate evidence about the standard norms in a community as well as the benefit of any programme that can influence them. GEMS has been adapted in rural South Africa and used to measure gender attitudes (Unhealthy alcohol use was screened by using the 10-item Alcohol Use Disorders Identification Test (AUDIT) scale ( | PMC10657496 |
Statistical analysis | anxiety, PTS | REGRESSION | First, we describe the baseline socio-demographic and clinical characteristics by study arm using descriptive statistical analysis. Second, we compared baseline socio-demographic and other baseline descriptors based on Chi-square to examine whether randomization was successful. Third, we conducted intention-to-treat (ITT) analysis on the men’s mental health outcomes at 12 and 24 months (mid-line and end-line) by fitting Generalized Estimating Equations (GEE) logistic regression models controlling for socio-demographic variables and baseline descriptors, setting anxiety and PTS as binary response with a logit link: g(µ | PMC10657496 |
Baseline socio-demographic and clinical characteristics by study arm | At baseline almost two-thirds of the men were unemployed ( | PMC10657496 |
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Impact of SS/CF on mental health | Our analyses (Mental health outcomes at 12 and 24 months according to intervention based on intention-to-treat based on generalized estimating equation.Mental health outcomes at 12 and 24 months according to intervention based on intention-to-treat based on generalized estimating equation after multiple imputation with 100 imputations. | PMC10657496 |
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Discussion | anxiety, PTS | RECRUITMENT | Our study examined the impact of SS/CF on young men’s mental health in urban informal settlements, the intervention being originally designed to reduce men’s perpetration of IPV (There are three potential mechanisms through which SS/CF impacted on anxiety and PTS. The first possible explanation could be due to it being an economic intervention that significantly strengthened young men’s livelihoods thereby alleviating poverty. Research has shown a connection between unemployment and poor mental health (Our investigation has several limitations, the first being that the evaluation of mental health outcomes was done using screening instruments, although it is unclear how screening measures would have impacted on the outcomes, as these were consistent across both arms. Secondly, this is a post-hoc data analysis of the intervention, which was primarily designed to improve IPV. Thirdly, the sampling techniques used (snowball and purposive) are forms of convenience sampling, which may negatively impact the generalizability of our findings. Data were also not collected for the number of individuals who were screened or refused to participate in the study. Individuals were not blinded to the study arm during recruitment, which might lead to recruitment bias. At the point of participant recruitment into the study, participants were aware which arm they were in, and this may have led to bias in recruitment. The lack of blinding was because the team were concerned that poor marginalized young people have often been promised support and not received it, and thus built-up resentment to broken promises. As such, there was no blinding. Despite attempts to locate participants, there was a difference in the follow-up by arm at end line, although multiple imputation was used to preserve statistical power and sample size. A higher attrition was detected among the intervention than the control group, although intention to treat analysis was used, where all participants were included in the final analysis. There are restrictions on how broadly our research can be generalized in other contexts, however this does not affect the validity of the results. The main outcomes paper describes the broader trial’s limitations ( | PMC10657496 |
References | PMC10657496 |
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Abstract | Ama Johal, Muftah Shagmani, Omar Alfuraih and Ian Arad contributed equally to this work. | PMC10803043 |
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Background and objectives | PLAQUE | To-date, there is no evidence comparing the long-term efficacy of powered and manual toothbrushes in adolescents undergoing fixed appliance treatment. The trial compared the efficacy of manual versus powered toothbrush in controlling plaque and gingival health in patients undergoing fixed treatment in respect of both the short- and long-term. | PMC10803043 |
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Trial design | This was a randomized, parallel, controlled single-blind clinical trial, undertaken in a hospital setting, for which the consolidated standards of reporting trials guidelines were followed. | PMC10803043 |
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Methods | bleeding | BLEEDING, PLAQUE | Ninety-two adolescent participants planned to undergo fixed appliance therapy, were randomly assigned to either a manual or powered toothbrush, with allocation concealment. The outcome measures were plaque and gingival indices and bleeding on probing, assessed at baseline (prior to fixed appliance), one-, six- and 12-months. | PMC10803043 |
Results | The final sample included 84 participants, aged 12-18 (M=14.1, SD=1.93) years, with 40 (47%) were using a manual and 44 (52%) a powered toothbrush. The intervention (powered vs. manual toothbrush) itself appeared insignificant with regards to the gingival index (GI) (95%CI −0.1 – 0.03; | PMC10803043 |
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Conclusion | PLAQUE | Whilst no differences were found between manual and powered toothbrushes in controlling plaque and gingival health, in participants undergoing fixed orthodontic treatment, both were suboptimal and highlighted the need for greater patient support and monitoring. | PMC10803043 |
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Trial registration details | PMC10803043 |
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Introduction | orthodontic, gingivitis, caries, tooth brushing | GINGIVITIS, DENTAL PLAQUE, CARIES, PERIODONTAL DISEASE, PLAQUE | Bacteria present in dental plaque are the primary aetiological agents in caries and periodontal disease. Therefore, effective tooth brushing remains an essential health practice to minimize plaque accumulation. Patients undergoing orthodontic treatment have greater difficulty in maintaining optimal oral hygiene levels, when compared with non-orthodontic patients, due to the presence of the appliances, increasing their susceptibility to gingivitis and enamel demineralization [The meta-analysis undertaken by Kaklamanos and Kalfas [Thus, to date, there is limited evidence comparing the efficacy of manual against powered toothbrushes in the short term (≤8 weeks) and importantly, no evidence comparing their efficacy in the long term in fixed appliance orthodontic patients.This study aims to compare the efficacy of a powered versus manual toothbrush in controlling plaque and gingival health in participants undergoing fixed orthodontic treatment in respect of both the short term and long term. | PMC10803043 |
Materials and methods | PMC10803043 |
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Participants, eligibility criteria, and setting | carious lesions | Ethical approval for this single-centre, hospital-based trial was granted by the National Research Ethics Services Committee (REC reference number: 14/LO/0003) and the trial registered (26.06.2014) with International Standard Randomised Controlled Trials Number (The study population was drawn from those due to receive comprehensive orthodontic treatment, with a pre-adjusted edgewise fixed appliances, who fulfilled the following inclusion criteria:Aged 12–18 years at the start of treatmentBrushed at least twice a dayGood general health and a non-smokerParticipants were excluded for the following reasons:They already used a powered toothbrushSpecial needs and learning difficultiesA history of periodontitis/attachment lossOral prophylaxis in the previous 4 weeksUse of antibacterial mouth rinses or antibiotic therapy within the past monthThe presence of five or more carious lesions requiring immediate restorative treatment. | PMC10803043 |
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Trial design and setting | This was a randomized, parallel, controlled single-blind clinical trial, undertaken in a hospital setting, for which the consolidated standards of reporting trials (CONSORT) guidelines were followed [ | PMC10803043 |
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Randomization, allocation concealment, and blinding | Participants who fulfilled the above selection criteria were identified and invited to take part in this study. Written informed consent and assent were obtained from the parent/guardian and participant, respectively. They were subsequently randomized (46 in each group) into either the intervention test (powered toothbrush) or control (manual toothbrush) groups (CONSORT flow diagram showing participant flow through the trial.An electronic randomization programme was used, whereby an equal allocation sequence was generated for the 92 participants meeting the initial acceptance criteria. The numbers were randomly assigned to either one of the two groups and placed in pre-prepared opaque envelopes, ensuring they were all identical and tamper evident. In the presence of a research nurse, a single envelope was then selected randomly by the participants and opened immediately following the placement of their appliances.The clinician assessing the outcomes was blinded to the randomization allocation, with a research nurse working independently to provide the oral hygiene instruction and to address any toothbrush or toothpaste replacement issues. Further blinding was undertaken during statistical analysis, aimed to further minimize bias. | PMC10803043 |
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Interventions | CAVITY | Following appliance placement, the research nurse provided participants with either an Omron-powered sonic toothbrush (PT) and Triple Clean head (ProClinical A1500, Omron Corporation, Kyoto, Japan) or an Oral B Indicator Medium 35 manual toothbrush (MT; Proctor and Gamble, USA). The powered toothbrush heads and manual toothbrushes were replaced every 3 months, in line with the study protocol and as recommended by the ADA Council of Scientific Affairs [All participants were provided Colgate cavity protection (Sodium Monofluorophosphate 1000 ppmF | PMC10803043 |
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Outcome measurements | gingivae, bleeding, inflammation, palate, tooth, trauma | PLAQUE, INFLAMMATION, BLEEDING, PLAQUE | Plaque and gingival scores assessed at baseline, before fixed appliance placement (T0), 1 month (T1), 6 months (T2), and 1 year (T3) along with an oral soft and hard tissue safety assessment. Data were collected by two trained and calibrated investigators (M.S. & O.A.) in the use of plaque and gingival indices.Plaque index (PI), gingival index (GI), and bleeding on probing (BoP) were recorded, at six sites per tooth, three on the buccal (mesio-buccal, mid-buccal, and disto-buccal), and three on the lingual tooth surfaces (mesio-lingual, mid-lingual, and disto-lingual) of the permanent dentition. Plaque scores were assessed using the Turesky modification of the Quigley–Hein plaque index (The Löe and Silness gingival index.Interpretation: severe (scores between 2.1 and 3.0), moderate (scores between 1.1 and 2.0), mild (score between 0.1 and 1.0), no inflammation (score of <0.1).The Turesky modification of the Quigley–Hein plaque index. The soft tissues (tongue, hard and soft palate, gingivae, muco-buccal folds, buccal mucosa, and floor of mouth) and hard tissues (orthodontic appliance attachments and the cervical portions of the teeth) were all assessed for trauma and or damage. | PMC10803043 |
Statistical analysis | PMC10803043 |
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Sample size calculation | According to the trial carried out by Clerehugh | PMC10803043 |
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Statistical methods | ’s mouth, bleeding, Tooth, tooth | REGRESSION, BLEEDING, PLAQUE | Data analysis was carried out using JMP®, Version 14 Pro (SAS Institute, Inc., Cary, NC, 1989-2019) software. The data (PI, GI, and BoP) were tested for normality and an intention-to-treat analysis was applied. The three primary outcomes (plaque scores, gingival index, and bleeding on probing) were collected per tooth, at each time point. The data were structured such that the unit of analysis was the specific tooth ‘nested’ within the participant’s mouth, repeated over time (1, 6, and 12 months). This approach allowed the outcomes per individual tooth to be monitored in the mouth, permitting a more detailed analysis rather than averaging measurements per person which would mask upfront the majority of the variance. The interactions were tested using parameter estimates. The details of the models applied are described below and included coefficients per each comparison. Therefore, a mixed-effects (fixed and random) multiple linear regression approach was chosen. Using the random coefficients, this approach allowed for an elaborate error framework in accordance with the nested structure of the data without violating the independency assumption, using the Restricted Maximum likelihood (REML) approach instead of the classical repeated measures structure, the model was capable of dealing with any missing observations (when individual teeth were not present e.g. second molars) while balancing their weight with respect to the variance. In these models, time point (1-, 6-, and 12-month time points) and tooth were regarded as within participant effects, while toothbrush was the only between participant effect. Applying the full factorial mixed-effects multiple linear regression strategy for each independent variable (at the tooth level). The model estimated included the following fixed effects: Toothbrush type, Time point, Tooth, Toothbrush × Time point, Toothbrush × Tooth, Time point × Tooth, Toothbrush × Time point × Tooth. In addition, the models included the following random effects: Subject No., Subject No. × Time point, and Subject No × Tooth; each nested within toothbrush type. This allows the estimation of each individual tooth as well as all of them together at the patient level. The data were analysed on an intention-to-treat basis, with all participants included, according to their original allocation, regardless of the outcome of treatment.The reproducibility of measurements for the two investigators was assessed using the interclass correlation coefficient. For all analyses, a | PMC10803043 |
Examiner alignment and assessment | tooth | RECRUITMENT | During examiner alignment, both examiners (M.S. and O.A.) and a research nurse (S.S.) were instructed and coached in the proper use of the outcome measurements (GI, BoP, and PI), before participant recruitment to the trial [A clinical assessment study to assess intra-examiner reproducibility of the measurements, was performed on 20 randomly selected participants. PI, GI, and BoP were recorded, at six sites per tooth, (described above), at the same visit with a 30-min interval. A weighted concordance Kappa’s index was performed to assess agreement between repeated measurements. Concordance of measurements was found to be good for GI (0.758, 95% CI 0.739–0.778) and BoP (0.77, 95% CI 0.753–0.796) and very good for PI (0.845, 95% CI 0.829–0.862). | PMC10803043 |
Results | PMC10803043 |
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Participant flow | RECRUITMENT, RECRUITMENT | Recruitment commenced in July 2014 and was completed in November 2017 (a 3-year 4-month rolling recruitment period). The recruitment and follow-up of all participants can be seen in the CONSORT flow diagram ( | PMC10803043 |
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Baseline data | bleeding | BLEEDING, PLAQUE | The final sample included 92 participants in the ages of 12–18 years (Baseline demographic and clinical characteristics of the sample (Descriptive statistics for gingival, bleeding on probing, and plaque indices for manual and power toothbrushes groups at each time point. | PMC10803043 |
Numbers analysed for each outcome | For the MT group, a total of 46, 41, 40, and 40 participant’s data were analysed at T0, T1, T2, and T3, respectively ( | PMC10803043 |
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Changes in outcome measures | ’s mouth, bleeding, tooth | REGRESSION, PLAQUE, BLEEDING, PLAQUE | The following section presents a separate analysis for each dependent variable: GI, PI and BoP from baseline (T0; immediately before placement of the fixed appliance) to 12-months (T3; Mixed-effects multiple linear regression for Gingival Index.
Model includes fixed effects for tooth and its interaction with time and toothbrush.Mixed-effects multiple linear regression for bleeding on probing.
Model includes fixed effects for tooth.Mixed-effects multiple linear regression for Plaque index.
Model includes fixed effects for tooth.The interaction observed between the specific tooth in the participant’s mouth and gingival index scores.The interaction observed between the specific tooth in the participant’s mouth and plaque index scores.The interaction observed between the specific tooth in the participant’s mouth and bleeding on probing scores.Spaghetti plots for mean Gingival Index, bleeding on probing, and Plaque Index to show changes over time and per tooth in the mouth. | PMC10803043 |
Gingival index | REGRESSION | The mixed-effects multiple linear regression was used to estimate the difference in GI scores across all participant teeth ( | PMC10803043 |
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Bleeding on probing | PMC10803043 |
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Plaque Index | In the mixed effects model for PI ( | PMC10803043 |
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